621 Lec 16 Clinical Relevance of Hepatic Function

FDA recommends PK studies in patients with hepatic impairment if…

FDA recommends PK studies in patients with hepatic impairment if…

• 20% of elimination by hepatic metabolism and/or excretion

• < 20% of elimination is hepatic but drug has narrow therapeutic range

• Unknown contribution of hepatic elimination route

What are the 3 determinants of hepatic clearance ?

hepatic blood flow (QH ), protein binding (fu ), and intrinsic clearance (CL’int)

Facors that Impact Hepatic Clearance:

Hepatocellular Enzyme/Transporter Activity

Protein Binding

Hepatic Perfusion

Determinants of Hepatic Clearance

1. Intrinsic clearance

2)Unbound (free) fraction of drug

3)Hepatic Blood flow

1. Intrinsic clearnace

•Enzyme or transporter activity

→Induction: increased number of enzymes

→Inhibition: Decreased number of enzyme molecules or inhibition of function

• Enzymes and pumps only act on free (unbound) drug

• Cirrhosis, diet, drug-drug interactions, genetic polymorphisms

2)Unbound (free) fraction of drug

•Unbound drug is pharmacologically active

•Unbound drug is form that is cleared

•Increased Fu when a drug with higher affinity for the protein is given, displacing the other

•Increased fu when plasma protein production decreases

•Increased fu can also increase drug distribution (Vd)

When Drug B with higher affinity for protein is given →

Drug A is displaced and fu increases

When plasma protein decreases (hypoalbuminemia) →

fu increases

When fu (fraction unbound) increases, Vd…

increases

3)Hepatic Blood flow

•Combination of portal vein (2/3) and hepatic artery (1/3)

•Flow impairment:

→Primary:Cirrhosis (liver scarring)

→Primary: Budd chiari syndrome

→Secondary: Heart failure

→Secondary: Hypotension/Hypoperfusion

Primary causes of flow impairment

cirrhosis, Budd Chiari Syndrome

Secondary causes of flow impairment

heart failure, hypotension, hypoperfusion, sepsis, volume depletion

Extraction Ratio

Ratio of the rate of drug elimination over the rate of drug entry for an organ of elimination

Hepatic Clearance equation

QH x ER

High extraction ratio IV Clearnace Hepatic

CLh = Qh

High extraction ratio for IV drugs

CLh = Qh

Low Extraction Ratio for IV drugs CL equation

CL = fu CLint

For IV drugs with low extraction ratio, what factors affect Css unbound

Cl int

For IV drugs with high extraction ratio, what factors affect Css unbound

Fu and Qh

For oral drugs, what factors affect Css unbound at high and low ER?

only CLint